Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer

Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer.     

Case of a 23-year-old woman with serous surface papilloma of borderline malignancy of the left ovary and mucinous cystadenoma of the right ovary

A rare case is reported of a 23-year-old woman with serous surface papilloma of borderline malignancy (SSPBM) of the left ovary associated with a foci of peritoneal “implant,” as well as the coexistence of mucinous cystadenoma of the right ovary. The histologic diagnosis of these tumors was classified according to the criteria of the World Health Organization. To confirm the histologic diagnosis, special staining was performed both with AIcian blue, periodic acid-Schiff (PAS), and PAS with diastase digestion, and with immunohistochemical staining for vimentin, cytokeratin, epithelial membrane antigen (EMA), neuron-specific enolase, and carbohydrate antigen 19-9 (CA 19-9). After hematoxylin and eosin staining of the tissue samples, the right ovarian tumor was diagnosed as benign mucinous cystadenoma, and the left ovarian tumor was identified as serous surface papilloma with no apparent stromal invasion, but showing proliferating activity and nuclear abnormality (SSPBM). The histologic features of the peritoneal lesion resembled those of the SSPBM of the left ovary, and showed no invasion of underlying normal tissue. Moreover, both the SSPBM and the peritoneal lesion showed similar patterns on special staining. The summary diagnosis was SSPBM of the left ovary associated with a foci of peritoneal noninvasive “implant” and coexistent mucinous cystadenoma of the right ovary. Regardless of whether or not the peritoneal loci represented an autochthonous multicentric tumor of the peritoneum or a secondary implant from the left SSPBM, the less aggressive histologic character of her tumors has allowed this patient to survive for 8 years after fertility-retaining surgery with no sign of recurrence.     

Borderline ovarian tumour: pathological diagnostic dilemma and risk factors for invasive or lethal recurrence

By comparison with ovarian carcinomas, borderline ovarian tumours are characterised clinically by superior overall survival, even in women with peritoneal spread. In this Review, we aimed to clarify the histological and clinical factors potentially defining a high-risk group in whom disease is likely to evolve to invasive disease. Invasive peritoneal implants (in serous borderline ovarian tumours) and residual disease after surgery were the two factors clearly identified. Other factors are controversial owing to increased risk of invasive recurrence: micropapillary patterns in serous borderline ovarian tumour, intraepithelial carcinoma in mucinous lesions, stromal microinvasion in serous lesions, and use of cystectomy in mucinous borderline ovarian tumours. The pathologist has a pivotal role in assessment of the borderline nature of ovarian tumours and in identification of high-risk criteria, most of which are histological. But, reproducibility of the histological interpretation of some of these potential criteria--eg, classification of peritoneal implants (particularly in desmoplastic subtype), stromal microinvasion, micropapillary patterns, and intraepithelial carcinoma in mucinous borderline ovarian tumours--remains unclear, and should be investigated.     

Molecular evidence for the independent origin of extra-ovarian papillary serous tumors of low malignant potential

BACKGROUND: Molecular data suggest that peritoneal tumors in women with advanced-stage ovarian papillary serous adenocarcinoma are monoclonal in origin. Whether the same is true for ovarian tumors of low malignant potential is not known. We compared peritoneal and ovarian tumors from women with advanced-stage ovarian papillary serous tumors of low malignant potential to determine whether the peritoneal tumors arose from the same clone as the ovarian tumors. METHODS: We studied the clonality of 73 peritoneal and ovarian tumors from 18 women with advanced-stage ovarian papillary serous tumors of low malignant potential. Formalin-fixed, paraffin-embedded tumors and representative normal tissues were sectioned and stained with hematoxylin-eosin, representative sections from separate tumors were manually microdissected, genomic DNA was extracted from the microdissected tumors, and the polymerase chain reaction was used to amplify a CAG polymorphic site in the human androgen receptor locus on the X chromosome to determine the inactivation pattern of the X chromosome and the clonality of the tumors. RESULTS: The pattern of X-chromosome inactivation could be determined from the tumors of 13 of 18 patients. Of the 13 patients, seven (54%) had nonrandom inactivation of the X chromosome, and six of the seven had different inactivation patterns in the peritoneal and ovarian tumors. Three of these patients also had different patterns of nonrandom X-chromosome inactivation in tumors from each ovary. The remaining six patients had random patterns of X-chromosome inactivation in the peritoneal and ovarian tumors. CONCLUSIONS: Our data suggest that peritoneal and ovarian tumors of low malignant potential arise independently.     

Serous ovarian, fallopian tube and primary peritoneal cancers: a comparative epidemiological analysis

Invasive serous cancers are diagnosed in the ovary, fallopian tube and peritoneum. It is widely believed that these are variants of the same malignancy but little is known about fallopian tube and primary peritoneal cancers. A comparison of risk factors for these tumor types may shed light on common or distinct aetiological pathways involved in these types of cancer. We investigated risk factors for the three cancers using data from a large Australian population-based case-control study. We included women with incident invasive serous ovarian (n = 627), primary peritoneal (n = 129) and fallopian tube (n = 45) cancer and 1,508 control women. Participants completed a comprehensive reproductive and lifestyle questionnaire. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Hormonal contraceptive use was inversely related to risk of all three cancers. Parity and breast-feeding were also inversely related to risk of serous ovarian and fallopian tube cancer. In contrast, parous women had an increased risk of peritoneal cancer (OR = 1.8, 95%CI 0.8-3.9), and increasing parity did not lower risk. There was also no association between breast-feeding and peritoneal cancer. However, obesity was associated with a doubling of risk for peritoneal cancer alone (OR = 2.1, 95%CI = 1.3-3.4). The strikingly similar patterns of risk for serous ovarian and fallopian tube cancers and the somewhat different results for primary peritoneal cancer suggest that peritoneal cancers may develop along a different pathway. These results also call into question the role of the physical effects of ovulation in the development of serous ovarian cancer.     

Rac1蛋白在人卵巢浆液性腺癌组织中的表达及其对卵巢癌细胞SKOV3迁移能力的影响

目的探讨Rac 1蛋白在人卵巢浆液性腺癌组织中的表达情况及其对卵巢癌细胞SKOV3迁移能力的影响。方法采用蛋白质印迹法(Western blot)检测59例卵巢浆液性腺癌组织、31例卵巢良性浆液性囊腺瘤组织和3 5例卵巢正常组织中Rac 1蛋白的相对表达量。筛选出抑制Rac 1蛋白表达效果最佳的载体,构建稳定转染细胞株SKOV3-Racli;采用细胞划痕实验检测SKOV3-Racli细胞的迁移能力。结果卵巢浆液性腺癌组织中Racl蛋白的相对表达量高于卵巢良性浆液性囊腺瘤组织和卵巢正常组织(P<0.05)。与阴性质粒比较,1号片段质粒的抑制率为12.59%,2号片段质粒的抑制率为56.48%,3号片段质粒的抑制率为73.68%。与野生型SKOV3组相比,SKOV3-Racli细胞组SKOV3-Racli细胞的迁移能力下降(P <0.05)。结论 Rac1蛋白对卵巢浆液性腺癌细胞迁移能力的影响可能与下调卵巢浆液性腺癌组织中Rac 1蛋白的表达有关。     

Therapeutic strategies in epithelial ovarian cancer

Ovarian cancer is the most lethal gynecologic malignancy. It appears that the vast majority of what seem to be primary epithelial ovarian and primary peritoneal carcinomas is, in fact, secondary from the fimbria, the most distal part of the fallopian tube.Treatment of epithelial ovarian cancer is based on the combination of cytoreductive surgery and combination chemotherapy using taxane and platinum. Although clear cell type is categorized in indolent type, it is known to show relatively strong resistance to carboplatin and paclitaxel regimen and thus poor prognosis compared to serous adenocarcinoma, especially in advanced stages. Irinotecan plus cisplatin therapy may effective for the clear cell adenocarcinoma.The larger expectation for improved prognosis in ovarian carcinoma is related to the use of the new biological agents. One of the most investigated and promising molecular targeted drugs in ovarian cancer is bevacizumab, a monoclonal antibody directed against VEGF. PARP inhibitor is another one. A few recent studies demonstrated positive results of bevacizumab on progression-free survival in ovarian cancer patients, however, investigation of molecular targeting drugs in patients with ovarian cancer are still underway.     

Expression and histopathological correlation of CCR9 and CCL25 in ovarian cancer

Ovarian carcinoma is the most lethal gynecological malignancy among women and its poor prognosis is mainly due to metastasis. Chemokine receptor CCR9 is primarily expressed by a small subset of immune cells. The interactions between CCL25 and CCR9 have been implicated in leukocyte trafficking to the small bowel, a frequent metastatic site for ovarian cancer cells. We have previously shown that ovarian cancer cells express CCR9 and play an important role in cell migration, invasion and survival in the presence of its natural ligand in vitro. In this study, we have evaluated the expression of CCR9 and CCL25 in ovarian cancer cells and clinical samples. Ovarian cancer tissue microarrays from University of Alabama at Birmingham and AccuMax were stained for CCR9 and CCL25. Aperio ScanScope was used to acquire 80X digital images and expression analysis of CCR9 and CCL25. Flow cytometry and the Image stream system were used to conform the expression of CCR9 and CCL25 in ovarian cancer cells. Our results show significantly higher (p<0.001) expression of CCR9 and CCL25 in serous adenocarcinoma followed by serous papillary cystadenoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, cystadenoma, mucinous boderline adenocarcinoma, clear cell carcinoma, granulosa cell tumor, dysgerminoma, transitional cell carcinoma, Brenner tumor, yolk sac tumor, adenocarcinoma and fibroma cases, compared to non-neoplastic ovarian tissue. Similar to tissue expression, CCR9 was also significantly expressed by the ovarian cancer cell lines (OVCAR-3 and SK-OV-3) in comparison to normal adult ovarian epithelial cell. We provide the first evidence that CCR9 and its natural ligand CCL25 are highly expressed by ovarian cancer tissue and their expression correlates with histological subtypes. Expression of this chemokine receptor and its ligand CCL25 within primary tumor tissue further suggests a potential role of this chemokine-receptor axis in ovarian cancer progression.     

BCL6与Lewisy在卵巢浆液性肿瘤中的表达及其临床意义

目的：检测 B 细胞淋巴瘤－6（B cell lymphoma 6,BCL6）与 Lewis y 抗原在卵巢浆液性肿瘤组织中的表达,探讨其表达与卵巢浆液性囊腺癌的临床病理参数、预后的关系及其临床意义。方法：采用免疫组织化
　　学 SP 法检测卵巢浆液性囊腺癌、卵巢交界性肿瘤、卵巢良性肿瘤以及正常卵巢组织中 BCL6与 Lewis y 的表达,分析其与卵巢浆液性囊腺癌的临床病理参数和预后的关系以及二者相关性。结果：BCL6蛋白在卵巢浆液性囊腺癌、卵巢交界性肿瘤、卵巢良性瘤以及正常卵巢组织中的高表达率之间均有明显的差异（P 均＜0．05）。Lewis y 抗原在卵巢浆液性癌中的表达明显高于卵巢良性瘤及正常卵巢组织（P 均＜0．05）。随着卵巢肿瘤恶性程度的逐步增高,BCL6和 Lewis y 的表达明显增高,且二者存在正相关性（r ＝0．359,P ＝0．023）。BCL6的表达随着 FIGO 分期增加而逐渐增加（P ＜0．05）。BCL6为影响卵巢癌预后的危险因素（P ＜0．05）。结论：随着卵巢肿瘤恶性程度的逐步增高,BCL6蛋白和 Lewis y 的表达明显增高,且二者存在正相关性。BCL6的表达与临床期别、淋巴结转移、分化等相关,并可以用于患者的预后监测。     

Quantitative analysis of follicle-stimulating hormone receptor in ovarian epithelial tumors: a novel approach to explain the field effect of ovarian cancer development in secondary mullerian systems

The role of FSHR expression in ovarian cancer development is not clear. We examined quantitative expression of FSHR in different types of OET, presumed precursor lesions and peritoneal implants and further discussed FSH as a key growth-promotion factor for the process of ovarian epithelial tumorigenesis. Thirty-five primary OET specimens, including 5 serous cystadenomas, 4 papillary serous cystadenomas, 9 SBTs and 17 serous carcinomas, were examined for quantitative FSHR expression. Ten paired samples (3 benign cystadenomas, 5 SBTs and 2 carcinomas) were obtained from several morphologically different areas, including benign-looking, borderline and cancerous areas in the same OETs, and from the remaining ovarian tissue and contralateral ovaries. Competitive RT-PCR was performed to measure the quantitative expression of FSHR in each tissue sample. FSHR expression levels were compared among nonpaired samples and within paired samples. We found that OSE had the lowest FSHR expression, whereas antral follicles had the highest level. Within benign OETs, papillary serous cystadenomas have 4.9-fold higher FSHR levels than nonpapillary serous cystadenomas. SBTs had the highest level of FSHR expression, which was 12.8-fold, 2.7-fold and 2.4-fold higher than that of serous cystadenomas, papillary serous cystadenomas and grade 1 carcinomas, respectively. A similarly high level of FSHR mRNA was found in peritoneal implants, which were associated with SBTs. FSHR levels among serous carcinomas decreased with an increase in carcinoma grade. Grade 3 carcinomas had the lowest FSHR level, which was similar to that of serous cystadenomas, while grade 1 carcinomas had 6.5-fold higher FSHR levels than those in serous cystadenomas. Our results suggest that not only serum FSH but also FSHR in ovarian epithelium may play important roles in ovarian OET development. Both the receptor and ligand may act in a synergistic way to promote tumor growth. The observation that high FSHR levels are present in peritoneal implants suggests that FSH may also play a similar role in the development of peritoneal serous tumors. From this perspective, circulating FSH may be considered a driving force in the field effect theory for the development of both ovarian neoplasms and their associated peritoneal implants. However, the exact role of FSH and/or FSHR in the development of epithelial tumors arising in both the ovary and peritoneum needs further investigation.     

Identification of anaplastic lymphoma kinase as a potential therapeutic target in ovarian cancer

Ovarian cancer is the leading cause of death from gynecologic cancer. Improvement in the clinical outcome of patients is likely to be achieved by the identification of molecular events that underlie the oncogenesis of ovarian cancer. Here we show that the anaplastic lymphoma kinase (ALK) is aberrantly activated in ovarian cancer. Using an unbiased and global phosphoproteomic approach, we profiled 69 Chinese primary ovarian tumor tissues and found ALK to be aberrantly expressed and phosphorylated in 4 tumors. Genetic characterization of these ALK-positive tumors indicated that full-length ALK expression in two serous carcinoma patients is consistent with ALK gene copy number gain, whereas a stromal sarcoma patient carries a novel transmembrane ALK fusion gene: FN1-ALK. Biochemical and functional analysis showed that both full-length ALK and FN1-ALK are oncogenic, and tumors expressing ALK or FN1-ALK are sensitive to ALK kinase inhibitors. Furthermore, immunohistochemical analysis of ovarian tumor tissue microarray detected aberrant ALK expression in 2% to 4% serous carcinoma patients. Our findings provide new insights into the pathogenesis of ovarian cancer and identify ALK as a potential therapeutic target in a subset of serous ovarian carcinoma and stromal sarcoma patients.     

Predicting biomarkers for ovarian cancer using gene-expression microarrays

Ovarian cancer has the highest mortality rate of gynaecological cancers. This is partly due to the lack of effective screening markers. Here, we used oligonucleotide microarrays complementary to approximately 12 000 genes to establish a gene-expression microarray (GEM) profile for normal ovarian tissue, as compared to stage III ovarian serous adenocarcinoma and omental metastases from the same individuals. We found that the GEM profiles of the primary and secondary tumours from the same individuals were essentially alike, reflecting the fact that these tumours had already metastasised and acquired the metastatic phenotype. We have identified a novel biomarker, mammaglobin-2 (MGB2), which is highly expressed specific to ovarian cancer. MGB2, in combination with other putative markers identified here, could have the potential for screening.     

Ki67、PTEN在卵巢浆液性肿瘤中的表达及临床意义

目的探讨卵巢交界性浆液性囊腺瘤组织中Ki67和PTEN的表达及其意义。方法采用免疫组化SP法,检测32例卵巢交界性浆液性囊腺瘤组织和26例卵巢浆液性囊腺癌组织中Ki67和PTEN表达,并与10例卵巢浆液性囊腺瘤和11例正常卵巢组织进行比较。结果 Ki67和PTEN在卵巢交界性浆液性囊腺瘤组织中阳性表达率分别为65.6%和93.8%,与卵巢浆液性囊腺瘤组织（分别为60.0%和100.%）比较,无统计学意义（P〉0.05）,而与卵巢浆液性囊腺癌组织比较有统计学意义（P〈0.05）。Ⅰ、Ⅱ期卵巢交界性浆液性囊腺瘤患者PTEN阳性表达率,与Ⅲ期患者比较,有统计学意义（P=0.03）,而Ⅰ、Ⅱ期卵巢交界性浆液性囊腺瘤患者Ki67阳性表达率,与Ⅲ期患者比较,无统计学意义（P〉0.05）。结论 Ki67和PTEN可能在卵巢交界性浆液性囊腺瘤的发生、发展中起重要作用,可能成为卵巢交界性浆液性囊腺瘤预后评价的指标。     

A retrospective study of advanced ovarian cancer in our ward

OBJECTIVE: To evaluate the efficacy of primary treatment for ovarian cancer from overall survival and progression-free survival. PATIENTS AND METHODS: A total of 28 patients with epithelial ovarian cancer in stages III and IV who were primarily treated in our ward from 1993 were examined retrospectively. The Kaplan-Meier method and Harrington-Fleming test were carried out for the cumulative survival rate and analysis. RESULTS: There were significant differences in the progression-free survival rate depending on whether or not optimal debulking was possible through primary treatment (p = 0.0128) and whether the histological diagnosis was serous adenocarcinoma (p = 0.038). In the serous adenocarcinoma group, the periods of both overall survival and progression-free survival were longer in treatment with taxanes and platinum than by other regimens, but in the endometrioid adenocarcinoma group, the period of progression-free survival was very short. CONCLUSIONS: Optimal debulking through primary treatment is critical in advanced ovarian cancer. Therapy with taxanes and platinum is efficacious for serous adenocarcinoma. The chemo-sensitivity of endometrioid adenocarcinoma is high, but the chemotherapeutic effect is only temporary.     

Changes in the expression of MMP2, MMP9, and ColIV in stromal cells in oral squamous tongue cell carcinoma: relationships and prognostic implications

Ovarian cancer is the most lethal gynecologic malignancy. It appears that the vast majority of what seem to be primary epithelial ovarian and primary peritoneal carcinomas is, in fact, secondary from the fimbria, the most distal part of the fallopian tube. Treatment of epithelial ovarian cancer is based on the combination of cytoreductive surgery and combination chemotherapy using taxane and platinum. Although clear cell type is categorized in indolent type, it is known to show relatively strong resistance to carboplatin and paclitaxel regimen and thus poor prognosis compared to serous adenocarcinoma, especially in advanced stages. Irinotecan plus cisplatin therapy may effective for the clear cell adenocarcinoma. The larger expectation for improved prognosis in ovarian carcinoma is related to the use of the new biological agents. One of the most investigated and promising molecular targeted drugs in ovarian cancer is bevacizumab, a monoclonal antibody directed against VEGF. PARP inhibitor is another one. A few recent studies demonstrated positive results of bevacizumab on progression-free survival in ovarian cancer patients, however, investigation of molecular targeting drugs in patients with ovarian cancer are still underway.     

Six new monoclonal antibodies to serous, mucinous, and poorly differentiated ovarian adenocarcinomas

Six monoclonal antibodies directed against ovarian adenocarcinoma were generated by use of 100,000 x g supernatants of Triton-X-100 solubilized extracts of ovarian serous adenocarcinoma as the antigen source. Immunoperoxidase preparation of frozen-sections and routinely processed paraffin section specimens revealed a highly restricted reactivity of these antibodies when tested with adult (n = 2) and fetal (n = 3) tissue types. Coreactivities were occasionally observed with epithelia of the kidney, mammary gland, and pancreas. One monoclonal antibody, Ki-OC I-6-2, cross-reacted only with epididymal epithelia. No coreaction occurred with normal tissue of the ovary, Fallopian tube, or uterus. All antibodies were additionally tested on 74 cases of nonovarian malignancies, 15 cases of ovarian metastases of nonovarian carcinomas, and 114 specimens of ovarian neoplasms other than carcinomas. Ki-OC I-6-2 had no cross-reactivity with these tumors except for one case of renal cell carcinoma. This monoclonal antibody recognized serous, mucinous, and poorly differentiated adenocarcinoma cell types. None of the six antibodies reacted with clear cell or endometrioid carcinoma. All were found to be of the IgG-1 subclass. The tumor antigen to which Ki-OC I-6-2 immunoreacted was estimated to have a molecular weight of 80 kilodaltons (KD).     

DUSP10和 BZW1在卵巢浆液性肿瘤中的表达及临床意义

目的：检测双特异性磷酸酶10（dual specificity phosphatase 10,DUSP10）和碱性亮氨酸拉链蛋白BZW1抗体（basic leucine zipper and W2 domain containing protein 1,BZW1）分子在卵巢浆液性肿瘤中的表达情况,结合临床分期和病理分化结果,初步探讨它们在卵巢浆液性腺癌发生、发展中可能起到的作用。方法：采用免疫组化（EnVision 法）检测卵巢上皮性肿瘤（良、恶性肿瘤）和人正常输卵管组织中 DUSP10和 BZW1分子的表达以及定位情况。结果：检测结果表明 DUSP10和 BZW1分子在人卵巢上皮性良、恶性肿瘤和人正常输卵管组织中均有表达,DUSP10在卵巢浆液性腺癌、卵巢浆液性腺瘤和正常输卵管组织中的阳性表达率分别为94.5%、86.9%和100%（P <0.01）。在卵巢浆液性腺癌中,DUSP10阳性表达率临床晚期高于早期（97.1% vs 92.1%,P <0.01）;在高分化、中分化和低分化中的阳性率分别为100%、85.7%和96.9%（P<0.01）。而 BZW1在这三种组织中的阳性表达率分别为57.5%、47.8%和77.7%（P <0.01）。在腺癌组织中,BZW1阳性表达率临床晚期低于早期（48.6% vs 65.8%,P <0.01）;在高分化、中分化和低分化中的阳性率分别为47.4%、52.4%和66.7%（P <0.01）。结论：DUSP10在卵巢浆液性腺癌临床分期的早期阳性表达率低于晚期,表达差异显著,说明 DUSP10在卵巢癌的发生过程中起到了一定作用;同样,BZW1在卵巢浆液性腺癌病理分级中的阳性表达率随着组织恶性程度的增加而增高,说明 BZW1在卵巢浆液性腺癌中起到了类似癌基因的作用。     

WT1 and WT1-AS genes are inactivated by promoter methylation in ovarian clear cell adenocarcinoma

BACKGROUND: Ovarian clear cell adenocarcinoma is associated with one of the poorest prognoses among human epithelial ovarian cancers. The authors hypothesized that Wilms tumor suppressor 1 gene (WT1) sense and antisense (WT1-AS) expression and their promoter methylation status could characterize ovarian clear cell adenocarcinoma from ovarian serous adenocarcinoma. METHODS: To test this hypothesis, ovarian cancer cell lines and 42 cancer tissues (17 clear cell and 25 serous adenocarcinoma) were analyzed for expression and methylation of WT1 and WT1-AS genes. RESULTS: These experiments demonstrated that all serous adenocarcinoma tissues expressed both WT1 and WT1-AS genes, although expression of these genes was lacking in clear cell adenocarcinoma. The WT1 and WT1-AS promoter were significantly methylated in clear cell adenocarcinoma (88.2% and 88.2%, respectively) compared with serous adenocarcinoma (24.0% and 20.0%, respectively). Significant correlation between methylation and mRNA expression status was observed for each gene. Also in agreement with these data, WT1 and WT1-AS negative ovarian cancer cell lines reexpressed these genes after treatment with the demethylating agent, 5-aza-2'-deoxycytidine. CONCLUSIONS: The current study shows that CpG hypermethylation is an important mechanism of WT1 and WT1-AS gene inactivation in ovarian clear cell adenocarcinoma. This is the first report that has demonstrated differential expression and methylation of WT1-AS in ovarian clear cell and serous adenocarcinomas. This study presents new molecular characterizations between these two types of adenocarcinoma and may provide insight as to why clear cell adenocarcinoma has a poorer prognosis than serous adenocarcinoma of the ovary.     

Psammocarcinome séreux agressif de l’ovaire : à propos d’un cas et revue de la littérature

Psammocarcinoma of ovary is a rare serous neoplasm characterized by extensive formation of psammoma bodies with ovarian stromal invasion. Rarely aggressive with invasion of the peritoneum or intraperitoneal viscera, it is linked to a better prognosis than conventional serous adenocarcinoma. It is characterized by a tumor cells with little cytological atypia and a low nuclear grade. Extensive medlar search showed presence of only 29 cases of psammocarcinoma of ovary reported till date. A new case of aggressive psammocarcinoma of ovary in 65 years old woman is reported.     

应用iTRAQ多重化学标记串联质谱技术筛选晚期卵巢浆液性腺癌组织中卡铂耐药相关蛋白

目的 利用同位素标记相对和绝对定量(iTRAQ) 技术筛选晚期卵巢癌组织中卡铂耐药相关差异表达蛋白,为临床个体化治疗奠定实验基础。方法 收集Ⅲ期低分化卵巢浆液性腺癌标本并通过ATP-TCA药敏试验检测卡铂敏感度。取卡铂敏感和耐药标本各15例, iTRAQ试剂标记,被标记的肽段进行高效液相色谱（HPLC）分离及质谱检测（MS）。结果 共鉴定出iTRAQ标记定量信息有755个显著差异表达的蛋白。卡铂耐药组与卡铂敏感组相比,上调1.2倍以上的蛋白429个;下调0.83倍以下的蛋白326个。上调蛋白中有osteopontin（OPN）、clusterin（CLU）、5'-nucleotidase（CD73）和tissue inhititor of metalloproteinases 1（TIMP1）等18个蛋白与肿瘤恶性行为及化疗耐药相关。结论 应用iTRAQ技术能筛选出多种与晚期卵巢癌卡铂耐药相关的差异表达蛋白,该技术对于肿瘤组织蛋白质组学的研究有很好的应用前景。